Many adult human organs are incapable of repairing tissue that has been damaged as a result of injury or disease. Following myocardial infarctions, strokes and a variety of degenerative diseases, there is no effective way of replacing the damaged or lost tissue by regenerative growth. Hence, improving the regenerative capacity of adult tissues would dramatically impact the clinical management of these medical conditions. Remarkably, these same tissues can regenerate in animals such as the zebrafish and the newt. Since the same type of tissue can regenerate in one animal but not another, important differences must exist between similar tissues in different species that allow regeneration in one case but not the other. The challenge is to be able to find ways to manipulate tissue that lacks or has lost the capacity to regenerate to become capable of regenerative growth once again. The basic mechanisms that regulate embryonic development, cell cycle regulation and apoptosis were elucidated using genetic studies in Drosophila, yeast and C. elegans. However, until now, it has been difficult to use these model organisms to study the mechanisms that regulate tissue regeneration. We have recently developed a system that allows the tools of Drosophila genetics to be used to identify genes that regulate the capacity for regenerative growth. By expressing a gene that can kill cells in a manner that is both spatially and temporally restricted, we can efficiently ablate portions of Drosophila imaginal discs and allow them to regenerate in situ without the need for complex surgical manipulations. Regeneration occurs efficiently at specific stages of larval development but cannot occur beyond a critical point during the third larval instar. We propose to look for changes in the expression of regulators of growth and cell-cycle progression that correlate with the loss of capacity for regenerative growth. We will conduct a large-scale genetic screen for mutations in specific genes that can enable regenerative growth at later stages of development (at a time when it normally does not occur). Using this approach we aim to find strategies that can be used to enhance a tissue's capacity for regenerative growth.